After their discovery in 1965 (A. D. Bangham et al., J. Mol. Biol. 1965, 13:238-253), liposomes became a promising tool for drug delivery. Since that period, many methodologies have been developed for liposomal compositions, efficient drug encapsulation and retention, stability and targeting (M. C. Woodle and D. D. Lasic, Biochim. Biophys. Act. 1992, 1113:171-199). After being loaded with the desired amount of drug and being stable enough to accumulate in the target site, the next step generally is to release the content of the liposomes in response to a specific stimulus at the target. It has been hypothesized that enhanced release at the target site will significantly improve the specificity and efficacy of a liposomal drug (D. C. Drummond et al., Pharmacol. Rev. 1999, 51:691-744; M. B. Bally et al., J. Liposomes Res. 1998, 8:299-335; D. B. Penske et al., Curr. Opin. Mol. Ther. 2001, 3:153-158).
Various strategies have been used for triggering liposomal release at the target site. Formation of channels and defects in the liposomal bilayer, lamellar-micellar or lamellar-hexagonal phase transition, lipid phase separation and liposome fusion are some examples (P. Meers, Adv. Drug Deliv. Rev. 2001, 53:265-272; D. C. Drummond et al., Prog. Lipid Res. 2000, 39:409-460; A. Asokan and M. J. Cho, J. Pharm. Sci. 2002, 91:903-913; C. J. Chu and F. C. Szoka, J. Liposome Res. 1994, 4:361-395; J. L. Thomas and D. A. Tirrel, Acc. Chem. Res. 1992, 25:336-342). All these efforts have been focused on the lipid components of the liposomes, and a very limited success has been achieved (X. Guo and F. C. Szoka, Acc. Chem. Res. 2003, 36:335-341).